Poly(CPP-SA) Anhydride As A Reactive Barrier Matrix Against Percutaneous Absorption Of Toxic Chemicals

ABSTRACT

The present invention relates to a protective agent suitable to protect the human skin against toxic materials, particularly against chemicals with nucleophilic sites. The active moiety is a polyanhydride derivative. The active transdermal retardant offers a barrier property and chemically and/or physically reacts with harmful chemicals to decrease percutaneous absorption. In the preferred embodiments, polyanhydride in its low molecular weight form reduced flux of nicotine and nitrofurazone significantly. Additionally, polyanhydride in its high molecular weight form prevented nicotine absorption and decreased nitrofurazone permeation dramatically. Moreover, the polyanhydride in its high molecular weight form reduced nitroglycerin flux to a lesser extent.

The current application claims a priority to the U.S. Provisional Patentapplication Ser. No. 61/453,640 filed on Mar. 17, 2011.

FIELD OF THE INVENTION

The present invention generally relates to application of apolyanhydride polymer as a transdermal retardant, which can decrease andeven prevent percutaneous absorption of chemicals specifically thosewith nucleophilic sites. This interactive polyanhydride polymer and itsfamily is applied prior to exposure on the skin to provide a protectivebarrier against chemicals.

BACKGROUND OF THE INVENTION

The skin is our largest organ and forms a fascinating and uniqueinterface between us and the outside world. The stratum corneum, theoutermost keratinized layer of thick-walled epidermal cells, is the mostimportant, as this serves as the barrier to both the ingress ofchemicals and other agents, microorganisms and dangerous substances, andthe egress of water. However, the skin is not a total barrier andtransdermal absorption can play a considerable role in the internalexposure of persons exposed to hazardous substances. Some chemicals aremore toxic topically than orally, at least in animals. Furthermore, manycompounds are absorbed to a greater degree from the skin than orally.

Dermal exposure to chemicals occurs in a wide variety of occupations,spanning agriculture, manufacturing, and industrial fields. Pesticides,solvents, and polycyclic aromatic hydrocarbons are some of the mainchemical groups that have been recognized as posing health problems bydermal absorption. Due to pesticides, low volatility, and persistence,the amount of material inhaled is likely to be low unless a particularlyvigorous application results in significant aerosol formation. Workersin market gardens and greenhouses can experience high dermal exposuresduring application or harvest where handling of vegetation coated withpesticide residues takes place. Despite widespread use of solvents, theyare able to irritate and permeate the skin and affect a number of targetorgans within the body, including the kidneys, liver, and nervoussystem. As solvents tend to be volatile, their toxicity may principallyresult from inhalation of vapor. However, the highly lipophilic natureof most solvents can also result in dermal uptake when deposited on theskin. On the other hand, chronic exposure to solvents, which isinevitable in many occupations, may lead to an impairment of the skinbarrier, so toxic substances are allowed to reach the reservoir of thestratum corneum, or even deeper layers of the skin. Skin represents asignificant route of entry for many chemical warfare agents, includingsulphur mustard (a skin damaging agent) and VX (an anticholinesterase or“nerve” agent) which represent a potential hazard to both public serviceand civilian populations and have allegedly been used by military andterrorist organizations. Many other materials may also be absorbedthrough the skin in significant amounts. These include mercury,isocyanates, polychlorinated biphenyls, acrylates, and pharmaceuticalproducts such as steroids and nicotine.

On the other hand, percutaneous absorption can be increased in variousways, such as by the application of skin product on damaged skin, heat,and other mechanisms that all can worsen the problem. In this view,personal protective equipments, including specific suits, face masks,gloves and overboots, provide an efficient protection against the liquidand vapor forms of most toxic chemicals. However, due to their relativetightness, protective equipments may induce physical and heat stress.Moreover, many gloves do not resist the penetration of low molecularweight chemicals. Some allergens are soluble in rubber gloves and canpenetrate the glove and induce severe dermatitis. Furthermore, the glovemembrane can be structurally modified by a solvent; this may lead tochanges in permeation behavior. For all these reasons, the “topical skinprotectant” strategy has been adopted. Theoretically, skin barriercreams retard or even prevent the penetration into the skin. Thesecreams can be seen as reinforcing the natural barrier function of theskin and they are developed to complement or replace protectiveequipments. However, different studies have revealed that often barriercreams do not fulfill their protecting behavior completely. It has beenshown that barrier creams can be considered to give poor skin protectionagainst the organic solvents investigated. Even some studiesdemonstrated penetration enhancement of the model penetrants throughskin treated with barrier creams compared to untreated skin. It is forthese reasons that there have been attempts to improve their efficacy.Special effort has been put on developing active substances that reducepercutaneous absorption of hazardous materials. It has been shown thatbeta-cyclodextrins may be usefully incorporated into a barrierformulation to reduce percutaneous absorption of toxic materials onoccupational exposure. Permeation retardation may be due tocomplexation. In another study, a barrier cream coded as HP01 containsreactive protectants that chemically react with sulphur mustard. It wasalso shown that β-cyclodextrin and polyethylene glycol 1540 decreasedthe permeation of nitroglycerin significantly by about 2-4 times. Theretardation effect is possibly due to hydrogen bonding between the modelpenetrant and the interacting polymers.

DESCRIPTIONS OF PRIOR ART

EP0223524B1 is an adhesive bandage composed of a mixture ofpolyanhydride and a drug used to protect a wound and deliver the drugtransdermally. The adhesive film-like material is 5-500 microns thick,contains a plasticizer, and contains 50% of water by weight. Thefunction of the invention is to form an adhesive coat on a wound and tofacilitate healing thereof with the incorporated drug. Unlike thepresent invention, the prior art contains a pharmaceutically activeagent to facilitate wound recovery.

EP200508B1 is an adhesive oral bandage comprising a soft adhesive filmthat is composed of an anhydride polymer. Similar to the first priorart, this prior art also contains a pharmaceutically active agent. Thisprior art, however, only adheres to the oral mucosa and not the entireskin organ.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide a topical skinretardant which can retard percutaneous permeability and absorbabilityof chemical hazards. The topical skin retardant is composed a singlepolyanhydride derivative polymer namedpoly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) in low molecularweight polymer (LMWP) form and high molecular weight polymer (HMWP)form. The chemical toxins or penetrants used in this disclosure arenitrofurazone, nicotine and nitroglycerin. These penetrants have beenused to illustrate the efficacy of a polyanhydride and its family as atransdermal retardant. The above-mentioned object and other objects ofthe present invention will be apparent from the detailed descriptionprovided hereinafter.

In one embodiment, the objectives of the present invention have been metby decreasing percutaneous permeability and absorption of activeingredients comprising high percutaneous permeability:

(a) the three model penetrants are nitrofurazone, nicotine, andnitroglycerin, of which the first two have nucleophilic sites and(b) the potential percutaneous retardants selected were LMWP and HMWP,

In a second embodiment, the effect of increasing concentration ofretardants on percutaneous permeability and absorption of activeingredients with high percutaneous absorption comprising:

(a) the model penetrants are nitrofurazone, nicotine, and(b) LMWP and HMWP concentration varied from 1 to 4% W/V (100 μl/cm2).

In a third embodiment, the effect of penetrant concentration on theretardation effect of LMWP and HMWP:

(a) the model penetrant is nitrofurazone and nitrofurazone concentrationvaried from saturated solution to 100 μg/ml and(b) the potential percutaneous retardants selected were LMWP and HMWP.

As it was reported, the polymer used in this study is compatible in theimplant form in human, let alone topical use, which makes it superior toother available skin retardants. It is non-toxic and safe for use, asshown by testing in animals and in humans (35). A quantity of justaround 7 ml of 4% HMWP is sufficient for one application over 20% ofbody surface. It is worth mentioning the retardation effect reportedhere, through application of LMWP and HMWP, which have a molecularweight of 15000 and 75000, respectively. However we developed a methodto synthesize the polyanhydride polymer with a molecular weight of up to300000 (data not shown) which could significantly improve theretardation effect and chemical and physical barrier properties of thestudied polymer.

The polymer can be considered to give good skin protection against othermaterials with potentially toxic effects which contain nucleophilicsites. Isocyclic amines (like aniline, nitroaniline, toluidine,xylidines, anisidine, N-methylaniline, N,N-dimethylaniline,p-phenylenediamine, β-naphthylamine and benzidine) are widely-usedindustrial chemicals in the production of dyes, pharmaceuticals,pesticides and rubber, etc. Several isocyclic amines have beenclassified as human carcinogens. The uptake of isocyclic amines at theworkplace occurs by inhalation and percutaneous absorption. Hydrazineand its derivatives, such as dimethylhydrazine and phenylhydrazine,rapidly penetrate the skin and these compounds are possible carcinogens.They should be regarded as skin exposure hazards. Morpholine andN-ethylmorpholine are primary irritants that are also suspected ofpossible carcinogenicity. Dioxane may rapidly penetrate the skin. Due tothe systemic toxicity and potential carcinogenicity, dioxane should beregarded as a skin absorption hazard (36). The novel characteristics ofthe present invention together with the above described objects will bemore clearly understood according to the detailed explanation andembodiments of the present invention herein below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates chemical structure of model penetrants (a:nitrofurazone, b: nicotine, c: nitroglycerin).

FIG. 2 illustrates the cumulative penetrated amounts of nitrofurazonefrom an aqueous solution (200 μg/ml) through rat skin, with or withoutLMWP and HMWP.

FIG. 3 illustrates the cumulative penetrated amounts of nicotine fromaqueous solution (500 μg/ml) through rat skin with or without LMWP andHWWP.

FIG. 4 illustrates the cumulative penetrated amounts of nitroglycerinfrom aqueous solution (200 μg/ml) through rat skin with or without LMWPand HMWP.

FIG. 5 illustrates the general structure of polyanhydride.

FIG. 6 illustrates the chemical structure ofpoly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid)

DETAILED DESCRIPTION OF THE INVENTION

All illustrations of the drawings are for the purpose of describingselected versions of the present invention and are not intended to limitthe scope of the present invention.

Polyanhydrides are a class of biodegradable polymers characterized byanhydride bonds that connect repeat units of the polymer backbone chain.The main application of polyanhydrides is in the medical device andpharmaceutical industry. The characteristic anhydride bonds inpolyanhydrides are usually decomposed in water. This decompositionresults in two carboxylic acid groups which are biodegradable componentseasily metabolized by the body. Biodegradable polymers such aspolyanhydrides are capable of releasing physically entrapped orencapsulated drugs by well-defined kinetics. Due to theirbiocompatibility and drug encapsulating properties, polyanhydrides areideal polymers used in drug delivery. Therefore, the majority of priorart thoroughly exploited the drug delivery aspect of polyanhydrides. Forexample, prior art EP0223524B1 and EP0200508B1 are dermal and oralbandages that utilize a polyanhydride as a drug delivery component. Thepresent invention, however, utilizes a polyanhydride to stop chemicalabsorption into the skin organ and membranes. Additionally, these priorart utilize polycarboxylic acid polymer alone or with maleic anhydride.The present invention, however, utilizes only a single polyanhydridepolymer.

The present invention is a transdermal retardant composed of a singlepolyanhydride derivative polymer namedpoly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) in low molecularweight polymer (LMWP) forms and high molecular weight polymer (HMWP)forms. The polyanhydride derivative polymer namedpoly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) has the chemicalstructure shown in FIG. 6, where m and n are integers from 2 to 200.Moreover, the polyanhydride derivative polymer namedpoly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) has the molecularweights ranging from 15000 to 75000. The transdermal retardant comprisesnot only the aforementioned polyanhydride derivative, but also variousvariations of the poly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid)and its polyanhydride family, which has the general chemical structureshown in FIG. 5, where R is a linear or branched organic moiety, and mand n are integers from 2 to 200 The polymer has been used as a modelfrom polyanhydride family as a transdermal retardant. The creation ofthe transdermal retardant is claimed along with methods of preparing andapplying the transdermal retardant. The transdermal retardant has beenmanufactured using the solvent casting method for preparation of aninvisible nanofilm on the skin.

The method of preparing and applying the transdermal retardant commenceswith mixing the transdermal retardant with chloroform and ether toformulate the final product, wherein 2% and 4% w/v of the transdermalretardant is mixed in chloroform. Subsequently, the final product isapplied to skin and allowed the chloroform to evaporate in warm air inless than 10 minutes. Finally, the transdermal retardant is allowed tosettle into skin while chloroform and ether evaporate. In the preferredembodiment, the thickness of the transdermal retardant is 100 μl/cm² or1 millimeter. Chloroform serves as a solvent and a carrier of thepolyanhydride polymer. Additionally, ether serves as a stabilizer to thetransdermal retardant. The transdermal retardant may be formulated invarious forms such as solvent, aerosol and semisolid.

As reported in Summary of Invention and Examples thereinafter, both lowmolecular weight polymer (LMWP) and high molecular weight polymer (HMWP)forms of the poly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) retardtransdermal diffusion of nitrofurazone, nicotine, and nitroglycerin.Therefore, the results illustrate the efficacy of the polyanhydride as atransdermal retardant.

Example 1

The retardation effect of LMWP and HMWP against the percutaneousabsorption of nitrofurazone through rat skin is demonstrated in thisexample. The study was performed ex vivo on a male Wistar rat skin. Eachrat was euthanized with chloroform vapor and the abdominal hair wasgently removed with an electric clipper. The abdominal skin excised asfull-thickness and was cleaned of extraneous tissue. For the experimentsthe skin was placed in home-made vertical Franz-type glass diffusioncells, while the stratum corneum was facing the donor compartment. Eachdiffusion cell was allowed to equilibrate with the receptor fluid for 24hrs prior to experiments at ambient temperature. Our preliminary studiesshowed that distilled water cannot provide a perfect sink condition fornitrofurazone, therefore, two other systems of a) Tween 20 aqueoussolution (1% w/v) and b) a mixture of distilled water, acetonitrile andtriethylamine buffer (79:20:1) were investigated and the latter waschosen as the receptor phase for nitrofurazone. This mixture issuggested as mobile phase for HPLC assay of nitrofurazone by USP (35)and the effect of this mixture as an enhancer was investigated here.Results showed that this system did not change the nitrofurazone fluxthrough rat skin when used in both donor and receptor phases. Thissolution could provide sink condition. Solubility of nitrofurazone inthis receptor phase was measured to be 668 μg/ml.

After the 24 hr equilibration phase, receptor phases were replaced withfresh phases and its temperature was set at 37.0±0.1° C. to providesurface temperature of 32° C. The retardants were applied to the donorphase as 2 and 4% w/v solution in chloroform (100 μl/cm²) and thesolvent evaporated in less than 10 min using warm air. The systems wereleft to settle and the final residues of chloroform to evaporate (asmuch as possible). Permeants were then applied to the donor phase asaqueous solutions of 200 μg/ml. Interval sampling was performed for 24hrs. Donor phase was replaced with fresh one at 13 hours. Permeatednitrofurazone of all samples was measured by UV spectrophotometry at 385nm. The results are shown in FIG. 2 and summarized in Table 1 below.

TABLE 1 Effects of low (LMWP) and high (HMWP) molecular weightpolyanhydride on permeation of nitrofurazone through rat skin (mean ±SD, n = 3-5). Lag-time Flux Flux P- Lag-time P- Treatment (μg/cm²/hr)FRR^(a) value (hr) LER^(b) value Q₂₄(μg/cm²)^(c) None 11.44 ± 1.62  13.53 ± 0.45 205.41 ± 28.02 (control) 2%(W/V) 5.31 ± 1.69 2.16 0.000 2.94± 1.04 0.83 0.244 107.63 ± 32.60 LMWP 4%(W/V) 4.44 ± 1.50 2.58 0.0001.77 ± 1.52 0.50 0.023  56.72 ± 30.54 LMWP 2%(W/V) 3.67 ± 0.04 3.120.000 6.97 ± 1.53 1.97 0.000 63.57 ± 5.46 HMWP 4%(W/V) 2.45 ± 0.45 4.670.000 9.01 ± 1.86 2.55 0.000 38.82 ± 5.63 HMWP ^(a)FRR: Flux retardationratio (control/treated) ^(b)LER: Lag time elongation ratio(treated/control) ^(c)Q24: cumulative amount of nitrofurazone permeatedafter 24 hr ^(d)k_(p): permeability coefficient

As shown in Table 1 above and FIG. 2, nitrofurazone showed a permeationflux of 11.4±1.6 (μg/cm²/hr) and lag-time of 3.5±0.4 (hr) in controlsamples. Retardant treatment decreased nitrofurazone flux and increasedits lag-time up to 4.7 and 2.6 times, respectively. The effects of bothpolymers at all concentration on nitrofurazone flux retardation (2.2-4.7times) were statistically significant (p<0.00). For the lag-timehowever, while LMWP at 2% did not show a significant effect (p>0.05),HMWP at both 2% and 4% was able to increase the lag time significantly(p<0.00) by about 2.0 and 2.6 times, respectively. In studies with LMWP,there was no delay in the appearance of penetrants in the receptorcompartment, which indicates that the preparation did not form aphysical barrier on the skin. However, after pretreatment with HMWP, theappearance of penetrants was delayed. These results suggest that thiscomposition also acted as a physical barrier.

Example 2

The retardation effect of LMWP and HMWP against the percutaneousabsorption of nicotine through rat skin is demonstrated in this example.The procedures in Example 1 were repeated using distilled water as thereceptor phase and aqueous nicotine solution of 500 μg/ml as the donorphase. Permeated nicotine of all samples was measured by UVspectrophotometry at 260 nm. Table 2 and FIG. 3 summarize the effects ofdifferent concentrations of low and high molecular weight polymers onpercutaneous absorption of nicotine through rat skin at 32° C.

TABLE 2 Effects of low (LMWP) and high (HMWP) molecular weightpolyanhydride on permeation of nicotine through rat skin (mean ± SD, n =3-5). Flux (μg/ Flux P- Q₁₀(g/ k_(p)(cm/ Treatment cm²/hr) FRR^(a) valuecm²)^(b) hr*10²)^(c) None 40.00 ± 6.97 1.00 — 319.82 ± 52.64 8.00 ± 1.39(control) 2%(W/V) 19.57 ± 3.07 2.04 0.006 193.88 ± 74.83 3.91 ± 0.61LMWP 2%(W/V) 15.62 ± 6.70 2.56 0.001 116.63 ± 45.10 3.12 ± 1.34 HMWP3%(W/V)  9.37 ± 3.43 4.27 0.000 24.48 ± 8.81 1.87 ± 0.69 HMWP 4%(W/V)NO^(d) — — NO NO HMWP ^(a)FRR: Flux retardation ratio (control/treated)^(b)Q₁₀: cumulative amount of nicotine permeated within 10 hrs^(c)k_(p): permeability coefficient ^(d)NO: not observed

Control (untreated) skin exhibited a nicotine steady-state flux of40.00±6.97 μg/cm²/hr. The presence of polymeric film from 2% (W/V) LMWPreduced the flux of nicotine significantly (P=0.006) by about 2 times.Application of 2% HMWP showed a higher retardation effect for permeationof nicotine (2.6 times, P=0.001). When the HMWP concentration wasincreased to 3%, it showed a low but detectable amount of nicotine inthe receptor phase at 2 and 3 hours, which stayed constant until the endof the experiments. At 4%, HMWP stopped permeation of nicotine throughrat skin completely, as no nicotine was observed in the receptorcompartment throughout the experiment.

Example 3

It was decided here to study the effect of penetrant concentration onthe retardation effect of LMWP and HMWP, based on the hypothesis thatthe complexation mechanism is affected by permeant concentration, whilea simple barrier effect does not. As nicotine and nitrofurazone havesimilar sites for nucleophilic attack, only one of these permeants(nitrofurazone) was used to investigate this hypothesis. The retardationeffect of LMWP and HMWP against the percutaneous absorption of 100, 200μg/ml and saturated solutions of nitrofurazone through rat skin isdemonstrated in this example. An absorption rate of 5.11±1.39 μg/cm²/hrwas measured with 100 μg/ml nitrofurazone in aqueous solution, and thisincreased further to 11.44±1.62 μg/cm²/hr and 18.24±1.51 μg/cm²/hr with200 μg/ml and saturated nitrofurazone in aqueous solution. This modelpenetrant also showed concentration-dependent lag time profile. Theprofile of the relationship between flux retardation ratio andconcentration of nitrofurazone indicated that flux retardation ratioincreased significantly with decreasing concentration of nitrofurazone(Table 3). The same profile, although to a lesser extent, was observedabout HMWP between lag time elongation ratio and nitrofurazoneconcentration (Table 4).

TABLE 3 Effects of different concentrations of nitrofurazone on fluxretardation efficacy of low (LMWP) and high (HMWP) molecular weightpolyanhydride through rat skin (mean ± SD, n = 3-5). Flux (μg/cm²/hr)Nitrofurazone 2%(W/V) P- 2%(W/V) P- concentration None(control) LMWPFRR^(a) value HMWP FRR^(a) value saturated 18.24 ± 1.51 14.28 ± 1.90 1.28 .006 12.31 ± 3.24  1.48 0.009 200 μg/ml 11.44 ± 1.62 5.31 ± 1.692.16 .000 3.67 ± 0.04 3.12 0.000 100 μg/ml  5.11 ± 1.39 1.69 ± 0.48 3.02.000 1.44 ± 0.31 3.55 0.000 ^(a)FRR: Flux retardation ratio(control/treated)

TABLE 4 Effects of different concentrations of nitrofurazone on lag timeelongation efficacy of low (LMWP) and high (HMWP) molecular weightpolyanhydride through rat skin (mean ± SD, n = 3-5). Lag time (hr)Nitrofurazone None 2%(W/V) P- 2%(W/V) P- concentration (control) LMWPLER^(a) value HMWP FRR^(a) value saturated 1.44 ± 0.56 2.00 ± 0.69 1.390.241 2.75 ± 0.71 1.92 0.012 200 g/ml 3.53 ± 0.45 2.94 ± 1.04 0.83 0.2446.97 ± 1.53 1.96 0.000 100 g/ml 4.17 ± 0.62 4.82 ± 4.43 1.16 0.745 6.51± 0.62 1.56 0.000 ^(a)LER: Lag time elongation ratio (treated/control)

Example 4

The retardation effect of LMWP and HMWP against the percutaneousabsorption of nitroglycerin through rat skin is demonstrated in thisexample. The procedures in Example 2 were repeated using aqueousnitroglycerin solution of 200 μg/ml as the donor phase. The amount ofpermeated nitroglycerin was measured using the Bell spectrophotometricmethod (37). Nitroglycerin was chosen as a model penetrant that does nothave nucleophilic sites. Table 5 and FIG. 4 summarize the effect of lowand high molecular weight polymer on percutaneous absorption ofnitroglycerin through rat skin.

TABLE 5 Effects of low (LMWP) and high (HMWP) molecular weightpolyanhydride on permeation of nitroglycerin through rat skin (mean ±SD, n = 3-5). Flux Flux(μg/ P- Q₁₀(μg/ kp (cm/ Treatment cm²/hr) FRR^(a)value cm²)^(b) hr*102)^(c) None 21.42 ± 5.77 1.00 — 110.20 ± 18.47 10.71± 2.88 (control) 2%(W/V) 20.99 ± 5.03 1.02 0.893 98.58 ± 6.86 10.50 ±2.30 LMWP 2%(W/V) 13.59 ± 3.52 1.58 0.036 99.93 ± 9.88  6.80 ± 2.12 HMWP^(a)FRR: Flux retardation ratio (control/treated) ^(b)Q₁₀: cumulativeamount of nitroglycerin permeated within 10 hrs ^(c)k_(p): permeabilitycoefficient

Penetration of nitroglycerin was not significantly changed in thepresence of polymeric film from 2% (W/V) LMWP (P=0.803). However,application of 2% HMWP led to a decrease of flux by 1.6 (P=0.036).Cumulative amount absorbed after 24 hrs in presence of LMWP and HMWP hasnot changed compared to untreated skin (P=0.293). In this example theutilization of higher molecular weight of this polymer which wassynthesized in our lab (data not shown) could be highly advantageous.

Although the invention has been explained in relation to its preferredembodiment, it is to be understood that many other possiblemodifications and variations can be made without departing from thespirit and scope of the invention as hereinafter claimed.

1. A transdermal retardant comprises a single polyanhydride derivative polymer named poly(1,3-bis(p-carboxyphenoxy)propane-sebacic acid) and/or any member from the polyanhydride family in a range of molecular weights.
 2. A method of preparing and applying a transdermal retardant comprises the steps of: (a) mixing the transdermal retardant with chloroform and ether to formulate the final product, wherein 2% and 4% w/v of the transdermal retardant is mixed in chloroform; (b) applying the final product to skin and evaporating chloroform with warm air within less than 10 minutes; and (c) allowing the transdermal retardant to settle into skin during evaporation of chloroform and ether residues.
 3. The method of preparing and applying a transdermal retardant as claimed in claim 1, wherein chloroform serves as a solvent and a carrier of the transdermal retardant.
 4. The method of preparing and applying a transdermal retardant as claimed in claim 1, wherein ether was added as a stabilizer to the transdermal retardant. 